Esters of 2,2-dimethyl-5-(aryloxy)-1-pentanols

ABSTRACT

Ester derivatives of 2,2-dimethyl-5-(2,5-xylyloxy)-1-pentanol and 2,2-dimethyl-5-(3,5-xylyloxy)-1-pentanol. These compounds lower serum triglyceride levels. They can be produced by reacting the 1-pentanol compounds with an esterifying agent.

United States Patent 1 Creger et al.

in] 3,759,986 Sept. 18, 1973 1 ESTERS 0F 2,2-D1METHYL-5-(ARYLOXY)-l-PENTANOLS [75] Inventors: Paul E. Creger; Winifred A. Neuklis,

both of Ann Arbor, Mich.

[73] Assignee: Parke, Davis & Company, Detroit,

Mich.

[22] Filed: Aug. 25, 1972 [21] Appl. No.: 283,863

Related [1.5. Application Data [62] Division of Ser, No. 24,000, March30, 1970, Pat. No.

[52] [1.8. CL... 260/488 CD, 260/465 F, 260/468 R, 260/471 C, 260/473,260/476 R, 260/521 R, 260/566 R, 260/600, 260/613 D, 424/300,

[51] Int. CL. C07c 67/00, C07c 69/14, C070 67/74,

Primary Examiner-Vivian Garner Attorney-Robert R. Adams et a1.

[57] ABSTRACT Ester derivatives of 2,2-dimethy1-5-(2,5-xylyloxy)1-pentanol and 2,2-dimethyl-5-( 3 ,5-xyly1oxy)- 1 pentanol. Thesecompounds lower serum triglyceride levels. They can be produced byreacting the pentanol compounds with an esterifying' agent.

3 Claims, No Drawings ESTERS OF 2,2-DlMETHYL--(ARYLOXY )-l-PENTANOLSThis is a division of application Ser. No. 24,000 filed Mar. 30, 1970,now US. Pat. No. 3,707,566.

SUMMARY AND DETAILED DESCRIPTION The present invention relates to new2,2-dimethyl-5- aryloxypentane compounds. More particularly, the inandto methods for their production. In this formula one of R and Rrepresents hydrogen; the other of R and R represents methyl; and Yrepresents cyano (-CN), formyl (-CHO), or a group of the formula inwhich R represents hydrogen, lower alkyl, an acyl radical of ahydrocarbon carboxylic acid containing not more than seven carbon atoms,or phenylcarbamoyl (C H NHCO). When R represents lower alkyl, it is alower alkyl radical of preferably notmore than 4'carbon atoms and ismost suitably methyl.

In accordance with the invention, the carbinols of the invention, thatis, the compounds wherein Y represents -CHOR- I and R representshydrogen, can be produced byreacting a compound ofthe formula Ha CH3with a reducing agent; where R and -R are as defined before and Rrepresents hydrogen, a salt-forming cation, or a lower alkyl radical ofpreferably not more than 4 carbon atoms. The preferred method ofcarrying out the reduction is by reacting the carboxylic acid, salt, orester with a complex metal hydride followed by or accompanied byhydrolysis of the product. Some examples of suitable complex metalhydrides are lithium aluminum hydride, lithium aluminum hydride-aluminumchloride, sodium borohydride-aluminum chloride, and sodiumbis(Z-methoxyethoxy)-aluminchydride. In the case where a lower alkylester is the starting material, it is also satisfactory to carry out thereductionwith sodium borohydride or to use a non-hydride reducing agentsuch as sodium in ethanol. The preferred reducing agent is lithiumaluminum hydride followed by hydrolysis of the product. Preferredsolvents for use with most of the complex metal hydrides named above,are ethereal solvents such as diethyl ether, tetrahydrofuran,1,2-dimethoxyethane, and diethylene glycol dimethyl ether. However, inthe case of sodium borohydride, preferred solvents are water, dioxane,lower alkanols such as ethanol, and mixtures thereof. The requir'edratio of reactants depends on the particular starting materials used.For example, reduction with lithium aluminum hydride requiresthree-quarters of a mole of lithium aluminum hydride for each mole ofcarboxylic acid or one-half mole of lithium aluminum hydride for eachmole of carboxylic'acid ester. However, these calculated ratios are notnormally employed as it is preferred to use a relatively large excess ofthe lithium aluminum hydride or other reducing agent. Thus, it iscustomary to use up to two moles of lithium aluminum hydride to reduceone mole of carboxylic acid or up to ten moles of sodium borohydride toreduce one mole of carboxylic acid ester. The time and temperature ofthe reaction are not particularly critical and likwise are dependent onthe specific reactants employed; In general, the reaction is carried outat a temperature between 0 C. and 120 C. or the reflux temperature ofthe solvent, with lithium aluminum hydride reductions preferably carriedout at about 35-65 C. and sodium' borohydride reductions preferablycarriedout at about C. The usual reaction time with lithium aluminumhydride is from 1 to 20 hours, optimally about 3 hours; and with sodiumborohydride from 17 to 30 hours, optimally about 22 hours. Followingreaction with a complex metal hydride in a non-aqueous solvent, themixture is hydrolyzed with water or other aqueous medium and the productisolated. In other cases, the product can be isolated directly.

The 2,2-dimethyl-5-aryloxyvaleric acids, salts, and esters employedasstarting materials-in the foregoing process can be prepared by any of avariety of methods. For example, an alkali metal derivative of acompound of the formula I CH:

Caron-coon is reacted with an aryloxypropyl halide of the formula whereR, R and R are as defined before and X represents halogen, preferablychlorine or bromine. The alkali metal derivative indicated above can beregarded as corresponding to the formula cm cm-r -coom where Mrepresents an alkali metal and R represents a salt-forming cation or alower alkyl radical. It is customarily prepared in situ by reactingisobutyric acid or a salt'or ester of isobutyric acid with a strong basesuch as lithium diisopropylamide. The reaction is preferably carried outin an anhydrous ethereal solvent followed by hydrolyzing the mixturewith water. When it is desired to isolate the product as an ester,prolonged exposure to the basic aqueous medium is avoided. In othercases, the product is isolated directly as a salt or, followingacidification, as the free acid. These procedures are illustrated ingreater detail hereinafter and in a copending application of Paul L.Creger, Ser. No.

819,126, filed Apr. 24, 1969, now US. Pat. No. 3,674,836, issued July 4,1972.

Also in accordance with the invention, the lower alkyl ethers of theinvention, that is, the compounds wherein Y represents 5 CH OR and Rrepresents lower alkyl; can be produced by reacting a compound of theformula CH: CH:

the formula where R represents an alkyl radical of preferably not morethan four carbon atoms. Some examples of such esters are methyl iodide,ethyl bromide, ethyl iodide, isopropyl bromide, butyl chloride, butyliodide, dimethyl sulfate, and methyl p-toluenesulfonate. Some examplesof bases suitable for use in the reaction are sodium hydride, sodiumamide, n-butyllithium, phenyllithium, and other strong bases of alkalimetals. A preferred base is n-butyllithium. Some examples of so]- ventssuitable for use in the reaction are diethyl ether, diethylene glycoldimethyl ether, dimethoxyethane, tetrahydrofuran, dimethylformamide,dimethyl sulfoxide, hexamethylphosphoramide, or an excess of the loweralkylating agent. A preferred solvent is dimethoxyethane. Although thereactants can be employed in approximately equimolar quantities, it ispreferred to use an excess of the lower alkylating agent. The time andtemperature of the reaction are not critical and depend somewhat on thereactants employed. In general, the reaction is carried out at atemperature from 0 to 150 C. or the reflux temperature of the solventfor from 2 to 48 hours. Using n-butyllithium as the base, the reactionis preferably carried out at a temperature of 0-35 C. for from 6 to 36hours.

Further in accordance with the invention the esters of the invention,that is, the compounds wherein Y rep resents -CH OR and R represents anacyl radical of a hydrocarbon carboxylic acid containing not more thanseven carbon atoms, or phenylcarbamoyl; can be produced by reacting acompound of the formula with a carboxylic acid of the formula Ac-OI-Isents the acyl radical of a hydrocarbon carboxylic acid containing notmore than seven carbon atoms. Some examples of suitable reactivederivatives of the hydrocarbon carboxylic acids are the acid halides andthe acid anhydrides. The reaction can be carried out in the absence ofan added solvent although, in general, the use of a solvent ispreferred. Some examples of suitable solvents are tertiary amines,tertiary amides, ethers, aromatic hydrocarbons, halogenatedhydrocarbons, ethyl acetate, or an excess of acid anhydride reactant.Some examples of preferred solvents are toluene, xylene, or excessanhydride reactant. The reactants can be used in approximately equimolarquantities although, in many cases, an excess of the carboxylic acid orits reactive derivative is preferred. In certain cases, it is desirableto carry out the reaction in the presence of a catalyst. When ahydrocarbon carboxylic acid is a reactant, a suitable catalyst isp-toluenesulfonic acid or other strong acid. When an acidhalide or acidanhydride is a reactant, a suitable catalyst is a tertiary amine such astriethylamine or pyridine. The time and temperature of the reaction aredependent on the specific starting materials used. In general, thereaction is carried out between room temperature and 175 C. or thereflux temperature of the solvent for from 1 to 96 hours, the longerreaction times being used at the lower temperatures. The preferredtemperature range is from to C. When one of the reactants is ahydrocarbon carboxylic acid, the progress of the reaction isconveniently followed by collecting the water formed in the reaction andcontinuing the reaction until the calculated amount of water has beencollected.

Still further in accordance with the invention, the nitriles of theinvention, that is, the compounds wherein Y represents cyano, can beproduced by reacting a 3- aryloxypropyl halide of the formula withisobutyronitrile in the presence of a base; where R and R are as definedbefore and X represents halogen. Some examples of suitable bases arealkali metal hydrides, alkali metal amides, alkali metal tertiaryalkoxides, and alkali metal triphenylmethides. Preferred bases arelithium tertiary amides, especially lithium di ethylamide or lithiumdiisopropylamide. Some examples of suitable solvents for the reactionare polar oxygenated solvents such as tetrahydrofuran, tetrahydropyran,dimethoxymethane, dimethoxyethane, diethylene glycol dimethyl ether, anddimethyl sulfoxide. Tetrahydrofuran is a preferred solvent for operatingat lower temperatures and diethylene glycol dimethyl e ther is apreferred solvent for operating at higher temperatures. The reactantscan be used in approximately equimolar quantities, especially when thebase is a lithium tertiary amide. When using other bases such as sodiumhydride, an excess of the 3-aryloxypropyl halide is preferred. Dependingon the specific reactants employed, the reaction can be carried out overa wide range of conditions, for example at a temperature from 50 to 175C. for from 1 hour to hours. According to the preferred conditions, thereaction is carried out wherein Y represents formyl, can be produced byreacting a compound of the formula with a hydrolytic agent; where R andR are as defined before and R represents a hydrocarbon radical orsubstituted hydrocarbon radical of not more than carbon atoms. Someexamples of hydrocarbon radicals which R" can represent are methyl,ethyl, isopropyl, butyl, tertiary butyl, hexyl, decyl, cyclopentyl,cyclohexyl, and methylcyclohexyl. When R represents a substitutedhydrocarbon radical the nature and number of substituents areunimportantas the group R is lost during the course of the reaction.Preferred examples of R are cyclohexyl and tertiary butyl. Some examplesof suitable hydrolytic agents are water, aqueous solutions of mineralacids such as hydrochloric acid, phosphoric acid, or sulfuric acid, andaqueous solutions of'organic acids such as acetic acid andp-toluenesulfonic acid. If desired, an organic solvent such astetrahydrofuran, a lower alkanol, or a lower alkanone can also bepresent. A preferred hydrolytic agent is aqueous hydrochloric acidoptionally in the presence of tetrahydrofuran or other organic solvent.At least the calculatedamount and preferably a large excess of thehydrolyticagent isused. The time and temperature of the reaction are notespecially critical. In general, the reaction is carried out' at atemperature from 0 to 125 C. or the reflux temperature for from 1 hourto 24 hours, the longer reaction times being used at the lowertemperatures. At a temperature of about 100 C. with dilute hydrochloricacid, the reaction is normally substantially complete within less than 4hours.

Starting materials required for use in the foregoing process can beprepared in any of a number of ways. For example, an imine of theformula is reacted with a 3-aryloxypropy1 halide of the formula in thepresence of lithium-diisopropylamide to producev an imine employed asstarting material in the process with, for example, dilute hydrochloricacid or other hydrolytic agent.

The compounds of the invention can exist in anhydrous form aswell as insolvated, including hydrated, forms. In general, the hydrated forms andthe solvated forms with pharmaceutically-acceptable solvents areequivalent to the anhydrous or unsolvated form for the V purposes of theinvention.

of the invention; where R, R, and R are as defined before, and Xrepresents halogen. If desired, the preparation of this startingmaterial can be carried out in situ and the reaction with the hydrolyticagent can be carried out directly by treatment of the reaction mixtureThe compounds of the invention are new chemical substances, of value aspharmacological agents which reduce serum triglyceride levels. Animportant property of these compounds is that they reduce serumtriglyceride levels without causing a corresponding reduction in serumcholesterol levels. The effectiveness of the compounds of the inventionin lowering serum triglycerides can be demonstrated by standard methods.For example, male rats weighing 200-250 g. are maintained on a normalpellet diet. Each animal in a treatment group is given a daily oral doseof a test compound for 7 days. Commonly a test compound is first studiedat a daily dose of 250 mg./kg. body weight; in subsequent groups ofrats, the dose is progressively lowered until the compound no longerexhibits significant activity. An untreated control group is alsomaintained. At the end of the 7-day test period the animals are weighedand sacrificed, and the serum cholesterol and serum triglycerides aredetermined from blood samples taken from the vena cava. The methods usedare described in Journal of Laboratory and Clinical Medicine, 50, 318(1957) and Journal of Laboratory and Clinical Medicine", 50, 152(-1957). The test compound is considered to exhibit a side effect if theweight of the animals in the treatment group is significantly less thanthe weight of the animals in the control group. In representativedeterminations, the following compounds of the invention at theindicated daily dose levels for 7 days produced the indicated reductionof serum triglycerides with no efiect on serum cholesterol or weight ofthe animals relative to the untreated control group.2,2-Dimethyl-5-(2,5-xylyloxy)-l-pentanol, 10 mg./kg. per day, 38 percentreduction of serum triglycerides; 2,2-dimethyl-5'( 3 ,5-xylyloxy)- 1-pentanol, mg./kg. per day, 64 percent reduction of serum triglycerides;2,2-dimethy1-5-(2,5-xylyloxy)valeronitrile, 250 mg./kg. per day, 39percent reduction of serum triglycerides. Other compounds of theinvention produce a significant reduction of serum triglycerides withinthe dosage range indicated above. Some of the preferred compounds of theinvention are the carbinols mentioned above. In addition toadministration by the oral route, as described above, the compounds ofthe invention can also be given by the parenteral route if desired.

The invention is illustrated by the following examples. Example 1 I Withstirring, a solution of 25.0 g. of 2,2-dimethyl-5- (2,5-xylyloxy)valericacid in 50 ml. of ether is slowly added to a mixture of 4.5 g. oflithium aluminum hydride and 300 ml. of ether. The resulting mixture isheated at reflux for 3 hours, cooled, and treated successively with 5ml. of water, 5 ml. of 15 percent sodium hydroxide solution, and 10 ml.of water. Insoluble inorganic material is removed by filtration. Thefiltrate is evaporated under reduced pressure to give a residue of2,2-dimethyl-5-(2,5-xyly1oxy)-1-pentanol. For purification, the productis distilled in vacuo; hp 1 15-1 17 C. at 20 microns n 1.5088.

By the foregoing procedure, with the substitution of 25.0 g. of2,2-dimethyl-5-(3,5-xylyloxy)va1eric acid for the2,2-dimethyl-5-(2,5-xy1yloxy)valeric acid, the product is2,2-dimethyl-5-(3,5-xylyloxy)-l-pentanol; b.p. 117-118 C. at 70 microns;n 1.5086.

Example 2 With stirring at C., 42 ml. of a 1.6 M solution ofn-butyllithium in hexane is added to a solution of 15.8 g. of2,2-dimethyl--(2,5-xylyloxy)-l-pentanol in 250 ml. of drydimethoxyethane. After an additional minutes stirring at 0 C., 28.5 g.of methyl iodide is added. The mixture is stirred for 18 hours at roomtemperature. An additional 28.5 g. of methyl iodide is added and themixture is stirred for hours more. It is then diluted with 250 ml. ofwater. The organic phase is separated, combined with an ether extract ofthe aqueous phase, dried over anhydrous magnesium sulfate, and filtered.The filtrate is concentrated under reduced pressure to give a residue ofl-methoxy-2,2- dimethyl-5-(2,5-xylyloxy)-pentane. For purification, theproduct is distilled in vacuo; b.p. l03-104 C. at 60 microns; n 1.4537.

By the foregoing procedure, with the substitution of 15.8 g. of2,2-dimethyl-5-(3,5-xylyloxy)-l-pentanol for the2,2-dimethyl-5-(2,5-xylyloxy)-1-pentanol, the product isl-methoxy-2,2-dimethyl-5-(3,5- xylyloxy)pentane; b.p. 108-109 C. at 70microns; n 1.4956.

Example 3 A mixture of 15.0 g. of2,2-dimethy1-5-(2,5-xylyloxy)-l-pentanol and 33.1 g. of acetic anhydrideis heated at reflux for 2 hours, cooled, and diluted with 200 ml. ofwater. The mixture is stirred for 2 hours and extracted with 200 ml. ofhexane. The organic phase is separated and washed with water, withsaturated aqueous sodium bicarbonate, and with water, dried overanhydrous magnesium sulfate, and filtered. The filtrate is concentratedunder reduced pressure to give a residue of2,2-dimethy1-5-(2,5-xylyloxy)-l-pentanol, acetate ester. Forpurification, the product is distilled in vacuo; b.p. l24l27 C. at 90microns; of 1.4891.

By the foregoing procedure, with the substitution of 15.0 g. of2,2-dimethyl-5-(3,5-xylyloxy)-l-pentanol for the2,2-dimethyl-5-(2,5-xy1y1oxy)-l-pentanol, the product is2,2dimethyl-5-(3,5-xylyloxy)-l-pentanol, acetate ester; b.p. l-l36 C. at50 microns. Example 4 A mixture of 23.6 g. of2,2-dimethyl-5-(2,5-xylyloxy)-1-pentanol, 12.8 g. ofcyclohexanecarboxylic acid, 1.5 g. of p-toluenesulfonic acidmonohydrate, and 250 ml. of toluene is heated at reflux for 18 hourswith continuous removal of the water formed in the reaction. The mixtureis cooled, diluted with 100 ml. of ether, washed with two 50 ml.portions of 2 N sodium hydroxide and with 100 ml. of saturated sodiumchloride solution, dried over anhydrous magnesium sulfate, and filtered.The filtrate is concentrated in vacuo to given a residue ofcyclohexanecarboxylic acid, 2,2-dimethyl-5- (2,5-xylyloxy)pentyl ester.For purification, the product is distilled in vacuo; b.p. l60-l62 C. at7 microns; n 1.5007.

Example 5 A mixture of 15.0 g. of2,2-dimethyl-5-(3,5-xylyloxy)-l-pentanol, 7.8 g. of benzoic acid, 1.0 g.of p-toluenesulfonic acid and 200 ml. of toluene is heated at reflux for62 hours with continuous removal of the water formed in the reaction.The mixture is cooled,

diluted with 100 ml. of water, and washed with saturated aqeuous sodiumbicarbonate and with water. The organic phase is dried and concentratedin vacuo to give a residue of 2,2-dimethyl-5-(3,5-xy1yloxy)-1- pentanol,benzoate ester; b.p. l68-171 C. at 40 microns; n 1.5321.

Example 6 A solution of 12.3 g. of2,2-dimethyl-5-(2,5-xylyloxy)-1-pentanol, 6.21 g. of phenyl isocyanate,and 200 ml. of toluene is heated at reflux for 62 hours. The mixture isconcentrated under reduced pressure to give a residue of2,2-dimethyl-5-( 2,5 -xylyloxy l -pentanol, carbanilate ester. Forpurification, the product is distilled in vacuo; b.p. 18720l C. at 70microns; n 1.5390; m.p. 60-62 C.

Example 7 With stirring and cooling at 0-l0 C., 248 m1. of a 1.61 Msolution of n-butyllithium in hexane is slowly added to a solution of40.4 g. of diisopropylamine in 350 ml. of anhydrous tetrahydrofuran. Theresulting mixture contains lithium diisopropylamide. After 10 minutes,27.6 g. of isobutyronitrile is added and after an additional 15 minutes,97.3 g. of 3-bromopropyl 2,5- xylyl ether (also known as3-(2,5-xylyloxy)propyl bromide) is added, the additions being made atsuch a rate that a temperature of 0-l0 C. is maintained. The resultingmixture is stirred at 30 C. for 18 hours and then diluted with 250 ml.of water. The organic phase is separated, dried over anhydrous magnesiumsulfate, and filtered. The filtrate is concentrated under reducedpressure to give a residue of 2,2-dimethyl-5-(2,5-xylyloxy)valeronitrile. For purification, the product is distilled invacuo; b.p. 1 l4-l20 C. at 60 microns; n 1.4975.

By the foregoing procedure, with the substitution of 97.3 g. of3-bromopropyl 3,5-xy1yl ether (also known as 3-(3,5-xylyloxy)propylbromide) for the 3- bromopropyl 2,5-xylyl ether, the product is 2,2-dimethyl-5-(3,5-xylyloxy)valeronitrile; b.p. l 15-l20 C. at 50 microns;n 1.5005.

Example 8 With stirring and cooling at 0-10 C., 248 ml. of a 1.61 Msolution of n-butyllithium in hexane is added to a solution of 40.4 g.of diisopropylamine in 350 ml. of anhydrous tetrahydrofuran. After 10minutes, 61.4 g. of N-(isobutylidene)cyclohexylamine is added and afteran additional 15 minutes, 97.3 g. of 3- bromopropyl 2,5-xyly1 ether(also known as 3-(2,5- xylyloxy)-propyl bromide) is added, the additionsbeing made at such a rate that a temperature of 0-10 C. is maintained.The resulting mixture is stirred at 30 C. for 18 hours. The mixture,which now contains N-[2,2-dimethyl-5-(2,5-xylyloxy)pentylidenelcyclohexylamine is heated atreflux for 4 hours with 300 ml. of 3 N hydrochloric acid. It is thencooled and extracted with ether. The ether extract is washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The filtrate is concentrated under reducedpressure to give a residue of 2,2-dimethyl-5-(2,5-xylyloxy)valeraldehyde. For purification, the product isdistilled in vacuo; b.p. 98104 C. at 30'microns.

By the foregoing procedure, with the substitution of 97.3 g.-of3-bromopropyl 3,5-xylyl ether (also known as 3-(3,5-xylyloxy)propylbromide) for the 3- bromopropyl 2,5-xylyl ether, the product is 2,2-

STARTING MATERIALS With stirring, 44.1 g. of isobutyric acid is added toa mixture of 51.0 g. of diisopropylamine, 23.2 g. ofa 57 percent sodiumhydride dispersion in mineral oil, and 350 ml. of tetrahydrofuran. Whengas evolution subsides, the mixture is heated at reflux for 15 minutes,cooled to C., and treated with 345 ml. of a 1.45 M solution ofn-butyllithium in heptane. After hours, the mixture is warmed one-halfhour at 30 C., cooled to 0 C., and treated with 122.0 g. of3-(2,5-xyly1oxy)-propyl bromide (also known as 3-bromopropy1 2,5-xylylether). Aferr 1 more hour, it is stirred with 500 ml. of water and theaqueous phase is separated and acidifed with 150 ml. of 6 N hydrochloricacid. The acidic mixture is extracted with ether and the ether extractis washed with saturated sodium chloride solution, dried over magnesiumsulfate, concentrated almost to dryness, and distilled in vacuo. Adistillate of 2,2-dimethy1- 5-(2,5-xy1yloxy)va1eric acid is collected atb.p. 158-159 C. at 0.02 mm. of Hg; m.p. (SI-63 C.fo11owingcrystallization from hexane.

The same product is obtained by substituting 4.4 g. of lithium hydridefor the sodium hydride in the above procedure.

The same product is also obtained in the following manner. A mixture of26.4 g. of isobutyric acid, 6.0 g. of magnesium oxide powder, and 250ml. of toluene is stirred and heated at reflux with continuous removalof the water formed in the reaction. When water formation ceases, theresulting mixture containing magnesium isobutyrate is concentrated toone-half its original volume, cooled in an ice bath, and treated with31.0 g. of diisopropylamine in 200 ml. of dry tetrahydrofuran and thenwith 179 ml. of 1.68 M n-butyllithium in heptane while the temperatureis maintained below C. After 15 more minutes, the mixture is warmed at30 C. for one-half hour, cooled to 0-10 C., and treated with 75.0 g. of3-(2,5-xylyloxy)-propyl bromide. The mixture is then stirred for 18hours at room temperature and diluted with ml. of 6 N hydrochloric acidand 250 ml. of water. The organic phase is separated, concentrated, andthe residue distilled in vacuo to give 2,2-dimethyl-5-(2,5-xy1y1oxy)valeric acid.

With stirring, 33.0 g. of dry sodium isobutyrate (prepared forisobutyric acid and sodium hydroxide) is added to a solution of 31.0 g.of diisopropylamine in 300 m1. of anhydrous tetrahydrofuran. Withexternal cooling to maintain the temperature below 10 C., 217 m1. of a1.45 M solutionof n-butyllithium in heptane is added. The mixture isthen stirred at 30 C. for one-half hour and treated with 75.0 g. of3-(3,5-xylyloxy)propyl bromide (also known as 3-bromopropyl 3,4-xylylether) dissolved in tetrahydrofuran. After 15 minutes, the mixture isallowed to warm to room temperature and stirring is continued for 16hours. The mixture is hydrolyzed with 500 ml. of water and the aqeuousphase is separated, washed with 200 ml. of ether, and acidified with 6 Nsulfuric acid to give 2,2-dimethy1-5- (3,5-xy1yloxy)va1eric acid as aninsoluble product. For purification, the product is dissolved in eitherand the ether solution is washed with water, dried over magnesiumsulfate, and evaporated. The product is crystallized from hexane; m.p.92-93 C.

We claim: 1. A compound of the formula Re R1 CH3 O-CH7CHg-CH7-CH30.-\C

dimethyl-5-(3,5-xylyloxy)- 1 -pentanol, acetate ester.

2. A compound according to claim 1 which is2,2-dimethyl-5-(2,5-xylyloxy)-1-pentanol, acetate ester.
 3. A compoundaccording to claim 1 which is 2,2-dimethyl-5-(3,5-xylyloxy)-1-pentanol,acetate ester.